Growth hormone, which is secreted from the pituitary, stimulate growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have following basic effects on the metabolic process of the body: 1) Increase the rate of protein synthesis in the cells of the body, 2) Decrease rate of carbohydrate utilization in the cells of the body; 3) Increase mobilization of the fatty acids and use of the fatty acids for the energy.
Artificial manipulation of growth hormone levels has been demonstrated to have significant therapeutic utility. Human growth hormone supplementation has been shown to be an effective treatment for growth hormone deficiency and their related diseases states in humans, such as short statue (Robinson and Clark., Growth Hormone: Basic and Clinical Aspect, Isaksspn, Binder, Hall and Hokfelt eds., Amsterdam, p109-127(1987).
Apart from this application, studies have uncovered new and significant properties of growth hormone which lend further importance to the ability to control growth hormone levels. For example, recent clinical studies indicate that growth hormone supplementation may be useful in combating the maladies of aging in humans. Elevated growth hormone levels in animals also have been shown to result in increase lean mass muscle. One application of this latter observation could results in higher production of leaner meat products or larger and/or stronger animals. However, their clinical and/or animal application, as with recombinant growth hormone, has been limited due to their high cost and lack of oral efficiency (Low, L. C. K., Neuroendoclinology, 1991,53 (Supp.1), 37-40: Thomer, M. O., Acta Pediatr 1993,388 (Suppl), 2-7).
The release of growth hormone from pituitary organs is under tight control of a second protein, growth hormone releasing factor (GRF), which is also commonly known in the art as somatomedin, growth hormone releasing hormone (GHRH), growth releasing hormone (GRH) and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. As a result, the development of synthetic growth hormone releasing agents and the use of drugs acting through established neurotrasmitter systems in the brain to stimulate growth hormone releasing are being considered as alternative to highly expensive and lack of oral efficiency growth hormone replacement therapy for the restoration on normal serum growth hormone levels (Pharm. Rev., 46,1-33(1994)).
Even before the discovery of the endogenous releasing factor GHRH in 1982 (Guillemin, R. et al., Science, 1982,218:585-587), Bowers and co-workers had reported on a series of peptides derived from Leu and Met enkephalins which specifically release growth hormone from pituitary (Bowers, C. Y. et al., Molecular Endoclinology. Maclntyne I (Ed.) Elsevier/North Holland Biomedical Press, Amsterdam 1977,287-292). It was later discovered that these growth hormone releasing peptides (GHRPs) act directly on the pituitary through a different signal transduction pathway from that of GHRH. In combination with GHRH, GHRPs act synergistically at the pituitary to release growth hormone. A hypothalamic binding site for GHRPs, which may be partially responsible for their growth hormone releasing in vivo by releasing endogenous GHRH, has been identified (Codd, E. E. et al., Neuropharmacology, 1989,28,1139-1144; Howard, D. H. et al., Science, 1996, 273, 974-976). Momany and Bowers employed molecular modeling techniques to discovered the growth hormone releasing hexapeptide GHRP-6, which is extremely potent and specific growth hormone secretagogue in human. More potent analogs of GHRP-6 have recently discovered and presently under clinical evaluation (Laron, A. Drugs, 1995,50,595-601). While GHRP-6 is a much more smaller peptide than either recombinant growth hormone or growth hormone releasing hormone, it still has low oral bioavailability in human (0.3%). However, GHRP-6 has demonstrated that relatively small molecule, with its possible advantage of lower cost and oral bioavailability, may be a viable alternative to subcutaneous treatment with recombinant growth hormone (DeVita, R. J. et al., Drugs of the Future, 1996,21(3), 273-281).
His-D-Trp-Ala-Trp-D-Phe-Lys-NH2GHRP-6 Ala-His-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2GHRP-1 D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2GHRP-2(KP-102) His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2Hexarelin
In recent years significant efforts have been taken to develop non-peptidyl analogs of this series of compounds. Such compounds, termed growth hormone secretagogues, should be orally bioavailable, induce production or release of growth hormone, and act as synergistically with growth hormone releasing hormone. Representative growth hormone secretagogues are disclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,248,841; U.S. Pat. No. 5,310,017; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,434,261; U.S. Pat. No. 5,552,385; U.S. Pat. No. 5,559,128; EP 144,230; EP 513,974; WO 94/07486; WO 94/08583; WO 94/11012; WO 94/13696; WO 95/03290; WO 95/09633; WO 95/12598; WO 95/13069; WO 95/14666; WO 95/16692; WO 95/16675; WO 95/17422; WO 95/17423; WO 95/34311; WO 96/02530; WO 96/05195; WO 96/13265; WO 96/15148; WO 96/22997; WO 96/24587; WO 96/35713; WO 96/38471; WO 97/00894; WO 96/24580; WO 97/06803; WO 97/07117; WO 97/11697; WO 97/15191; WO 97/22620; WO 97/23508; WO 97/24369 and Science, 260,1640-1643 (1993).
U.S. Pat. No. 5,206,235 issued Apr. 27, 1993, describes a series of benzolactam compounds typified by the following structure. These compounds have demonstrated
clinical activity in humans in raising the growth hormone secretory levels (B. J. Gertz., Journal of Clinical Endocrinology and Metabolism, 77,1393-1397(1993)).
Second generation of growth hormone secretagogues is described in WO 94/13696, WO 96/15148. These compounds are typified by the following structure.

A number of these compounds are reported to be safe and effective in promoting endogenous growth hormone release in humans, however, there remain problems with oral availability and specificity.